The goal of the project is to produce satisfactory protocols in the treatment of Duchenne muscular dystrophy (DMD) through a specific aim: define the long term effects of IL-6 blockade on both skeletal and cardiac muscle.
One of the candidates that contribute to sustain an hostile microenvironment in dystrophic muscle is Interleukin-6 (IL-6), a critical player in the switch from acute to chronic inflammatory response. Previous studies suggest that: i) increased levels of IL-6 exacerbate the pathological phenotype of mdx mice; ii) blockade of endogenous IL-6 receptor, with neutralizing antibody, confers on dystrophic muscles resistance to degeneration.
Our working hypothesis is that the hostile dystrophic niche might interfere with and limit the efficacy of dystrophin replacement interventions. Thus, any therapeutic strategy aims to restore dystrophic muscle is unlikely to promote satisfactory results unless the hostile niche is modified.
Based on previous and preliminary data and in order to safely propose a therapeutic intervention aimed at blocking IL-6 transignaling in humans, we will define the long term-mediated effect of IL6r-alpha ablation on dystrophic skeletal and cardiac muscles. The achievement of this project will establish the viability of IL-6 as a therapeutic target opening a new perspective in the treatment of DMD.
The anti-inflammatory agents glucocorticoids (GC) are the only available treatment for DMD. However, long-term GC treatment causes muscle atrophy and wasting. Thus, targeting specific mediator of inflammatory response may be more efficacious and with fewer side effects. The inflammatory cytokine IL-6 is overproduced in patients with DMD and in mdx mice. Preliminary work demonstrated that blockade of endogenous IL6r conferees on dystrophic muscle resistance to degeneration. In this project we will test the long term effects of IL6r ablation on dystrophic skeletal and cardiac muscles and verify whether IL-6 blockade will enhance survival and activity of the rescued dystrophic muscles. The information derived by this study will have an impact on the immediate translation of IL-6 blockade in the pharmacological treatment of DMD patients, since IL6R inhibitors are already available and their use have been recently approved in children with systemic juvenile idiopathic arthritis.